Extract from the Clinical Evaluation Report for Alogliptin：从阿格列汀临床评估报告提取物

DateoffirstroundCER:20January2013

DateofsecondroundCER:23April2013AusPARAttachment2ExtractfromtheClinicalEvaluationReportforAlogliptin(asbenzoate)ProprietaryProductName:Nesina,VipidiaSponsor:TakedaPharmaceuticalsAustraliaPtyLtd

AbouttheTherapeuticGoodsAdministration(TGA)TheTherapeuticGoodsAdministration(TGA)ispartoftheAustralianGovernmentDepartmentofHealth,andisresponsibleforregulatingmedicinesandmedicaldevices.TheTGAadministerstheTherapeuticGoodsAct1989(theAct),applyingariskmanagementapproachdesignedtoensuretherapeuticgoodssuppliedinAustraliameetacceptablestandardsofquality,safetyandefficacy(performance),whennecessary.TheworkoftheTGAisbasedonapplyingscientificandclinicalexpertisetodecision-making,toensurethatthebenefitstoconsumersoutweighanyrisksassociatedwiththeuseofmedicinesandmedicaldevices.TheTGAreliesonthepublic,healthcareprofessionalsandindustrytoreportproblemswithmedicinesormedicaldevices.TGAinvestigatesreportsreceivedbyittodetermineanynecessaryregulatoryaction.Toreportaproblemwithamedicineormedicaldevice,pleaseseetheinformationontheTGAwebsite<://.au>.AbouttheExtractfromtheClinicalEvaluationReportThisdocumentprovidesamoredetailedevaluationoftheclinicalfindings,extractedfromtheClinicalEvaluationReport(CER)preparedbytheTGA.ThisextractdoesnotincludesectionsfromtheCERregardingproductdocumentationorpostmarketactivities.MinorerrorsintheoriginalCERtexthavebeencorrectedforthisExtract.Thewords[Informationredacted],wheretheyappearinthisdocument,indicatethatconfidentialinformationhasbeendeleted.ForthemostrecentProductInformation(PI),pleaserefertotheTGAwebsite<://.au/hp/information-medicines-pi.htm>.Copyright©CommonwealthofAustralia2013

Thisworkiscopyright.Youmayreproducethewholeorpartofthisworkinunalteredformforyourownpersonaluseor,ifyouarepartofanorganisation,forinternalusewithinyourorganisation,butonlyifyouoryourorganisationdonotusethereproductionforanycommercialpurposeandretainthiscopyrightnoticeandalldisclaimernoticesaspartofthatreproduction.ApartfromrightstouseaspermittedbytheCopyrightAct1968orallowedbythiscopyrightnotice,allotherrightsarereservedandyouarenotallowedtoreproducethewholeoranypartofthisworkinanyway(electronicorotherwise)withoutfirstbeinggivenspecificwrittenpermissionfromtheCommonwealthtodoso.RequestsandinquiriesconcerningreproductionandrightsaretobesenttotheTGACopyrightOfficer,TherapeuticGoodsAdministration,POBox100,WodenACT2606oremailedto<tga.copyright@.au>.ContentsListofabbreviations 51. Introduction 92. Clinicalrationale 92.1. Formulationdevelopment 102.2. Guidance 102.3. Overseasregulatoryhistory 103. Contentsoftheclinicaldossier 103.1. Scopeoftheclinicaldossier 103.2. Paediatricdata 113.3. Goodclinicalpractice 114. Pharmacokinetics 114.1. Studiesprovidingpharmacokineticdata 114.2. Summaryofpharmacokinetics 154.3. Evaluator’soverallconclusionsonpharmacokinetics 225. Pharmacodynamics 225.1. Studiesprovidingpharmacodynamicdata 225.2. Summaryofpharmacodynamics 225.3. Evaluator’soverallconclusionsonpharmacodynamics 236. Dosageselectionforthepivotalstudies 236.1. Dataondosefrequency 236.2. Dosefindingstudies 237. Clinicalefficacy 257.1. Pivotalefficacystudies 257.2. Supportivestudies 817.3. Analysesperformedacrosstrials(pooledanalysesandmeta-analyses) 877.4. Evaluator’sconclusionsonclinicalefficacyinT2DM 878. Clinicalsafety 898.1. Studiesprovidingevaluablesafetydata 898.2. Pivotalstudiesthatassessedsafetyasaprimaryoutcome 898.3. Patientexposure 898.4. Adverseevents 928.5. Laboratorytests 1058.6. Post-marketingexperience 1118.7. Safetyissueswiththepotentialformajorregulatoryimpact 1138.8. Evaluator’soverallconclusionsonclinicalsafety 1139. Firstroundbenefit-riskassessment 1149.1. Firstroundassessmentofbenefits 1149.2. Firstroundassessmentofrisks 1159.3. Firstroundassessmentofbenefit-riskbalance 11610. Firstroundrecommendationregardingauthorisation 11611. Clinicalquestions 11611.1. Pharmacokinetics 11611.2. Pharmacodynamics 11611.3. Efficacy 11711.4. Safety 11712. Secondroundevaluationofclinicaldatasubmittedinresponsetoquestions 11713. Secondroundbenefit-riskassessment 11913.1. Secondroundassessmentofbenefits 11913.2. Secondroundassessmentofrisks 11913.3. Secondroundassessmentofbenefit-riskbalance 11914. Secondroundrecommendationregardingauthorisation 119

ListofabbreviationsAbbreviationMeaningADRadversedrugreactionAEadverseeventALTalanineaminotransferaseANCOVAanalysisofcovarianceAUC0-tareaundertheplasmaconcentration-timecurvefromthetimeofdosing(0hour)tothetimeofthelastquantifiableconcentrationAUC0-24areaundertheplasmaconcentration-timecurvefromthetimeofdosing(0hour)to24hoursafterdosingAUC0-48areaundertheplasmaconcentration-timecurvefromthetimeofdosing(0hour)to48hoursafterdosingAUC0-infareaundertheplasmaconcentration-timecurveextrapolatedtoinfinityAUEC0-tareaundertheeffect-timecurvefrom0hourtothetimeofthelastquantifiableeffectAUEC0-24areaundertheeffect-timecurvefrom0hourto24hoursafterdosingAUEC0-48areaundertheeffect-timecurvefrom0hourto48hoursafterdosingBLQbelowthelimitofquantitationBMIbodymassindexCavgpostprandialplasma(glucose)concentrationsCavgBpostprandialplasma(glucose)concentrationsfollowingbreakfastCavgLpostprandialplasma(glucose)concentrationsfollowinglunchCavgDpostprandialplasma(glucose)concentrationsfollowingdinnerCavgAllpostprandialplasma(glucose)concentrationsaveragedacrossallthreemealsCIconfidenceintervalCLrrenalclearanceCL/FapparentplasmaclearanceCmaxmaximumplasmaconcentrationCrCLcreatinineclearanceCVcoefficientofvariationCYPcytochromep450DAEdiscontinuationduetoadverseeventDBPdiastolicbloodpressureDPP-IVdipeptidylpeptidaseIVECEthicscommitteeECGelectrocardiogrameCRFelectroniccasereportformEmaxmaximumobservedeffectEminminimumobservedeffectFASfullanalysissetFDAFoodandDrugAdministrationFe%0-24fractionofthedoseexcretedunchangedintheurinefrom0to24hoursafterdosingFBCfullbloodcountFBGfastingbloodglucoseFPGfastingplasmaglucoseGIPglucose-dependentinsulinotropicpeptideGLP-1glucagon-likepeptide1HbA1cglycosylatedhaemoglobinHDL-ChighdensitylipoproteincholesterolHIVhumanimmunodeficiencyvirusHOMA-BCFhomeostasismodelassessmentofβ-cellfunctionHOMA-IRhomeostasismodelassessmentofinsulinresistancehs-CRPhighsensitivityC-reactiveproteinIASIntegratedAnalysisofSafetyICAMintracellularadhesionmoleculeIRBInstitutionalReviewBoardITTintent-to-treatIVRSinteractivevoiceresponsesystemLDL-ClowdensitylipoproteincholesterolLOCFlastobservationcarriedforwardLSleastsquaresMACEmajoradversecardiovasculareventMedDRAMedicalDictionaryforRegulatoryActivitiesMETmetforminMTDMaximumtolerateddoseNYHANewYorkHeartAssociationPgpp-glycoproteinPPSperprotocolsetQTccorrectedQTintervalQTcFcorrectedQTintervalusingthemethodofFridericiaRaccumulationratioSAEseriousadverseeventSDstandarddeviationSEstandarderrorSUsulfonylureaTEAEtreatmentemergentadverseeventt½apparentterminaleliminationhalf-lifeTmaxtimetoachievemaximumplasmaconcentrationormaximumeffectTZDthiazolidinedioneVCAMvascularcelladhesionmoleculeV/FapparentvolumeofdistributionXU0-24cumulativeamountexcretedintheurinefrom0to24hoursafterdosing

IntroductionThisisaCategory1Applicationtoregisteranewchemicalentity,NESINA/VIPIDIA(alogliptin[asbenzoate])6.25mg,12.5mgand25mgfilm-coatedtabletblisterpacks.Alogliptinisanorallyavailable,potent,andhighlyselectivedipeptidylpeptidase-4(DPP-4)inhibitorforthetreatmentofType2DiabetesMellitus(T2DM).TheproposedindicationsforNESINA/VIPIDIAare:Add-oncombination:NESINA/VIPIDIAisindicatedtoimproveglycaemiccontrolinadultpatients(≥18yearsold)withtype2diabetesmellituswhendietandexercisedonotprovideadequateglycaemiccontrol,asaddontometformin,asulphonylurea,athiazolidinedione,metforminandathiazolidinedione,orinsulin(withorwithoutmetformin).Initialcombination:NESINA/VIPIDIAisindicatedforuseasinitialcombinationwithmetformintoimproveglycaemiccontrolinadultpatients(≥18yearsold)withtype2diabetesmellituswhendietandexercisedonotprovideadequateglycaemiccontrolanddualalogliptinandmetformintherapyisappropriate.Theproposedtherapeuticdoseofalogliptinisone25mgtablettakendaily.Lowerdailydosepresentationswillbemadeavailableforpatientswithmoderaterenalimpairment(12.5mg)orend-stagerenaldisease(6.25mg).ClinicalrationaleThesponsorhasprovidedthefollowingrationaleforthedevelopmentofalogliptin:“T2DMisachronicconditionresultingfromthreedistinctdeficiencies:impairedinsulinsecretion,insulinresistanceandhypersecretionofglucagon.T2DMisassociatedwithanumberoflong-termmicrovascularandmacrovascularcomplications.TheUnitedKingdomProspectiveDiabetesStudyGroupshowedthattheriskofmicrovascularcomplicationswasdramaticallyreducedamongpatientswithT2DMwhenanHbA1ctargetlevelof<7%wasachieved(UKPDS,1999UKProspectiveDiabetesStudy(UKPDS)GroupIparedwithconventionaltreatmentandriskofcomplicationsinpatientswithtype2diabetes(UKPDS33).Lancet1998;352:837–53.).CurrentpharmacologicinterventionsforT2DMincludeadiverserangeofantidiabeticmedicationswithdifferentmechanismsofactionincludinginsulinandinsulinanalogues,sulfonylureas,biguanidessuchasMET,meglitinides,thiazolidinediones(TZDs),inhibitorsofalpha-glucosidase,analoguesofglucagon-likepeptide-1(GLP-1),dipeptidylpeptidase-4(DPP-4)inhibitors,andsyntheticanaloguesofhumanamylin.Despitethevarietyofantidiabeticmedications,manypatientshavedifficultyachievinganHbA1ctargetlevelof<7%duetosideeffects,restricteduse,long-termtolerabilityissues,orcomplianceissuesresultingfromsideeffects,routeofadministration,andpillburden.Duringthefirst3yearsofmonotherapywithafirst-lineoralantidiabeticmedication,upto50%ofpatientsexhibitinadequateglycaemiccontrol(Inzucchi,2002InzucchiSE.Oralantihyperglycemictherapyfortype2diabetes.JAMAUKProspectiveDiabetesStudy(UKPDS)GroupIparedwithconventionaltreatmentandriskofcomplicationsinpatientswithtype2diabetes(UKPDS33).Lancet1998;352:837–53.InzucchiSE.Oralantihyperglycemictherapyfortype2diabetes.JAMA2003:287;360-372.However,thereareseveralDPP-IVinhibitorscurrentlyapprovedforthetreatmentofT2DMinAustralia(includinglinagliptin,saxagliptinandsitagliptin).FormulationdevelopmentAdifferentformulationwasusedinthePhase2andPhase3studiestothatintendedformarketinginAustralia.Bioequivalencewasdemonstratedfortheseformulations.GuidanceTherewerenoformalpre-submissionmeetingsbetweentheSponsorandtheTGA.TheSponsordidseekadvicefromtheTGAontheprovisionofdatafromStudiesSYR-322-305andSYR-322-402.OverseasregulatoryhistoryAlogliptinwasapprovedformarketinginJapanon16thApril2010.AnapplicationwaslodgedintheUSon27thDecember2007buttheFDArequiredaCardiovascularSafetyStudytobeconductedinaccordancewithFDAGuidanceforIndustry:DiabetesMellitus-EvaluatingCardiovascularRiskinNewAntidiabeticTherapiestoTreatType2Diabetes.Areapplicationwaslodgedon25thJuly2011buttheFDAhadidentifiedapotentialsignalforhepaticsafetywithalogliptin,precludingapprovalofalogliptinproductsatthattime.TheFDAhasrequestedadditionalpost-marketingdatafromoutsidetheUSaswellasadditionalclinicaldatatoprovidereassuranceofthehepaticsafetyprofile.TheSponsorplannedtolodgeafurtherapplicationinJuly2012thatwouldincludethesamedatapackageassubmittedinEUandplannedforAustralia.However,itisnotexplicitlystatedintheAustralianDossierthetypeofdatarequestedbytheFDA(andspecificallywhetherthisincludesdetailsofpotentialcasesofdruginducedliverinjury)andwhethersuchdataareincludedintheAustralianDossier.AnapplicationwaslodgedintheEUon4thMay2012.AtthetimeoflodgingtheAustralianapplication,similarapplicationshadnotbeenlodgedinSwitzerland,CanadaorNewZealand.TheSponsorstatesthatModules2–5oftheDossiersubmittedinAustraliaareidenticaltotheEuropeanMAAsubmittedtotheEMAonthe4thMay2012.HoweverthewordingoftheproposedindicationinEuropeisdifferentfromtheproposedindicationforAustraliaanddoesnotincludetheuseasinitialcombinationwithMET.Consequently,theDossierdoesnotmakereferencetothisindicationandStudyMET-302isconsideredasupportivestudyintheEUMAAdocumentation.ContentsoftheclinicaldossierScopeoftheclinicaldossierThedossierrepresentsafulldevelopmentprogramforanewmedicalentity.Thesubmissioncontainedthefollowingclinicalinformation:Module5:28clinicalpharmacologystudies,including28thatprovidedpharmacokineticdataandfivethatprovidedpharmacodynamicdata.Onepopulationpharmacokineticanalysis.Ninepivotalefficacy/safetystudies,including:ThreeasaddontoMET:StudySYR-322-MET-008,StudySYR-322-MET-302,StudySYR-322-305Oneasadd-ontoSU:StudySYR-322-SULF-007Twoasadd-ontoTZD:StudySYR-322-TZD-009,Study01-06-TL-322OPI-002Twoasmonotherapy:StudySYR-322-PLC-010,StudySYR-322-303Oneasadd-ontoinsulin:StudySYR-322-INS-011TherewerenostudiesthatusedotherDPP-IVinhibitorsascomparators.Onedose-findingstudy:StudySYR-322-003Tenotherefficacy/safetystudies:StudySYR-322-301;Study01-05-TL-322OPI-001;Study01-06-TL-322OPI-004;StudySYR-322-OLE-012;StudySYR-322-308;StudySYR-322-CCT-001/StudySYR-322-OCT-001;StudySYR-322-CCT-003/StudySYR-322-OCT-003;StudySYR-322-CCT-004/StudySYR-322-OCT-004;StudySYR-322-CCT-005/StudySYR-322-OCT-005(SU);StudySYR-322-CCT-006/StudySYR-322-OCT-005(MET)Threesafetystudies:StudySYR-322-402,StudySYR-322-004andStudySYR-322-019ThreePSURs,anIntegratedSummaryofEfficacy,andanIntegratedSummaryofSafetyModule1:Applicationletter,applicationform,draftAustralianPIandCMI,andRiskManagementPlan.Module2:ClinicalOverview,SummaryofClinicalEfficacy,SummaryofClinicalSafetyandliteraturereferences.PaediatricdataThesubmissiondidnotincludepaediatricdata.GoodclinicalpracticeTheclinicalstudiespresentedintheDossierarestatedtohavebeen,andappeartohavebeen,conductedaccordingtoGCP.PharmacokineticsStudiesprovidingpharmacokineticdataConventionalPKanalysesTable1showsthestudiesrelatingtoeachpharmacokinetictopic.Table1.Submittedpharmacokineticstudies.PKtopicSubtopicStudyIDMainobjectiveofthestudyPKinhealthyadultsGeneralPK--SingledoseStudySYR-322-103AbsolutebioavailabilityStudySYR-322-001AscendingdoseStudySYR-322/CPH-001MetabolismStudySYR-322/CPH-002MetabolismStudySYR-322-014Massbalance-Multi-doseStudySYR-322-101Bioequivalence†-SingledoseStudySYR-322-027CommercialformulationFoodeffectStudySYR-322-02625mgdoseStudySYR-322/CPH-006StudySYR-322-CPH-007StudySYR-322-005PKinspecialpopulationsTargetpopulation§SingledoseNone-Multi-doseStudySYR-322-002TargetpopulationPKHepaticimpairmentStudySYR-322-023HepaticimpairmentRenalimpairmentStudySYR-322-006RenalimpairmentNeonates/infants/children/adolescentsNoneElderlyStudySYR-322-022GeneralPKStudySYR-322/CPH-003GeneralPKGenetic/gender-relatedPKMalesversusfemalesStudySYR-322-022GeneralPKPKinteractionsMET,cimetidineStudySYR-322-005Interactioncaffeine,tolbutamide,dextromethorphan,midazolam,fexofenadineStudySYR-322-015Interactionketoconazole,fluconazole,gemfibrozilStudySYR-322-016InteractionPioglitazoneStudySYR-322-017InteractionGliburideStudySYR-322-018InteractionCyclosporinStudySYR-322-020InteractionWarfarinStudySYR-322-021InteractionEthynyloestradiol,norethindroneStudySYR-322-024InteractionAtorvastatinStudySYR-322-025InteractionDigoxinStudySYR-322-029InteractionVogliboseStudySYR-322/CPH-004InteractionPopulationPKanalysesHealthysubjectsNoneTargetpopulationStudySYR-322-met-008-002342-1

Noneofthepharmacokineticstudieshaddeficienciesthatexcludedtheirresultsfromconsideration.PopulationPKanalysisObjectiveoftheanalysisStudySYR-322-met-008-002342-1wasapopulationPKanalysisofoncedailyorallyadministeredalogliptininsubjectswithT2DM.TheobjectiveofthestudywasdevelopastructuralpopulationPKmodelforalogliptininsubjectswithT2DM,toperformcovariateanalysestoexploresourcesofvariabilityinPKparameters,andtogeneratePKparameterestimatesandcalculateindividualexposuremeasuresusingthefinalpopulationPKmodel.DataThedatawereobtainedfromasinglePhase3trialofeitheralogliptin12.5mgor25mgoncedaily,incombinationwithMET.Therewere527subjects.Twobloodsamples(onetrough,onenon-trough)wereobtainedfromeachsubject.Thecovariatedatawere:age,weight,BSA,CrCL,sex,race,andconcomitantCYP2D6substrates,CYP2D6inhibitors,andrenalcationtransportersubstrates.Therewere840alogliptinconcentrationsfrom398subjectsavailableforanalysis.Medianagewas56years(range23to80years).Weightrangedfrom45.5to141.6kg,withamean(SD)of88(19.1)kg.MedianHbA1catBaselinewas7.7%(range,6.3%to10.2%).Morethanhalfofthesubjectshadmildrenalimpairment(CrCLbetween50and80mL/min)andaboutonethirdhadnormalrenalfunction(CrCL>80).Followingexclusionof52(6.2%)alogliptinconcentrationsfrom23(5.8%)subjectsasoutliers,therewere788alogliptinconcentrationsfrom375subjectsusedformodellingpurposes.MethodsBasedonexploratorydataanalysis(usingplotsoftimevsconcentration)andpriorPKstudies,atwocompartmentmodelparameterizedintermsofka,CL/F,centralvolumeofdistribution(Vc)/F,intercompartmentalclearance(Q),andperipheralvolumeofdistribution(Vp)wasemployedasthebasemodel.Howeverthefinalmodelappearstobewrittenasanon-compartmentalmodel.Interindividualvariability(IIV)foreachPKparameterwasestimatedusinganexponentialerrormodel.Aproportionalerrormodelwasusedtodescriberesidualerror(RV).ThepopulationPKanalysiswasperformedusingNONMEM,VersionVI.TheinfluenceofcovariatesonselectedPKparametersforalogliptin(CL/FandVc/F)wasevaluatedusingastandardforwardselectionandbackwardeliminationstrategy.Missingcovariatedatawereimputedusingpriororsubsequentobservations,orthepopulationmedian.Alogliptinconcentrationsbelowthelevelofquantificationwereexcludedfromtheanalysis.Covariateswheremorethan10%ofthedataweremissingwereexcludedfromtheanalysis.Modelselectionandhypothesistestsusedachangeintheminimumvalueoftheobjectivefunction(MVOF)ofatleast3.84(α=0.05,1degreeoffreedom)todefinestatisticalsignificancefortheadditionofasingleparameter.Results:ThebasemodelestimatedthepopulationmeanCL/Fas18.1L/hourwith%SEMof2.2;andVc/Fas148Lwith%SEMof11.1.Thefinalmodelwasasfollows(Figure1):

Figure1.PopulationPKbasemodelWhere:TVCL/Fi=thetypicalvalueoftheapparentoralclearancefortheithsubject;TVVc/Fi=thetypicalvalueoftheapparentcentralvolumeofdistributionfortheithsubject;CrCLi=creatinineclearanceintheithsubject;WTKGi=weight(kg)fortheithsubject.HenceincreasingCrCLandincreasingweightresultedinincreasedCL;andVcalsoincreasedwithweight.Age,sex,race(whiteversusotherthanwhite),CYP2D6inhibitors,CYP2D6substrates,andrenalcationtransportersubstrateswerenotincludedinthefinalmodel.ThefinalpopulationPKmodelforalogliptinpredicteda15%reductioninCL/Fforsubjectswithmildrenalimpairment,anda30%reductioninalogliptinCL/Fforsubjectswithmoderaterenalimpairment,comparedwithsubjectswithnormalrenalfunctionAUCandCmaxwereproportionaltodose.TheVPCsindicatedagoodfitforthemodeltotheobserveddata.SummaryofpharmacokineticsTheinformationinthefollowingsummaryisderivedfromconventionalpharmacokineticstudiesunlessotherwisestated.PhysicochemicalcharacteristicsoftheactivesubstanceThefollowinginformationisderivedfromtheSponsor’sProductInformationdocumentinModule1:Alogliptinbenzoateisawhitetooff-white,crystallinepowder,containingoneasymmetriccarbonintheaminopiperidinemoiety.Itissolubleindimethylsulfoxide,sparinglysolubleinwaterandmethanol,slightlysolubleinethanol,andveryslightlysolubleinoctanolandisopropylacetate.PharmacokineticsinhealthysubjectsAbsorptionSitesandmechanismsofabsorptionAlogliptiniscompletelyandrapidlyabsorbedfromthegastrointestinaltract.BioavailabilityAbsolutebioavailabilityDoseadjustedmean(90%CI)ratiooral/intravenousforAUC0-24was102.42(98.72to106.26)%(StudySYR-322-103.Doseadjustedmean(90%CI)ratiooral/intravenousforCmaxwas42.38(38.39to46.79)%.BioavailabilityrelativetoanoralsolutionormicronisedsuspensionBioavailabilityofthetabletformulationwas100%.BioequivalenceofclinicaltrialandmarketformulationsForthe12.5mgdosethemean(90%CI)fortheratiocommercial/Phase3forAUC0-infwas101.40(99.62to103.20)%andforCmaxwas89.20(81.92to97.14);andforthe25mgdoseforAUC0-infwas100.49(98.73to102.28)%andforCmaxwas104.75(98.50to111.38)(StudySYR-322-027).BioequivalenceofdifferentdosageformsandstrengthsTherewasnoformaltestingofbioequivalenceforthedifferenttabletstrengths.Howevertheformulationshad100%bioavailability.BioequivalencetorelevantregisteredproductsNotapplicable.InfluenceoffoodForthe25mgdose,themean(90%CI)fortheratioFed/FastedforAUC0-24was97.59(95.00to100.25)%andforCmaxwas103.41(92.38to115.75)%(StudySYR-322-026.ThemedianTmaxwas1.98hoursinthefedstateand1.51hoursinthefasted.InJapanesemalevolunteers,fora50mgoraldose,themean(90%)CIfortheratioofAUC0-inffed/fastedwas0.951(0.904to1.000)(StudySYR-322/CPH-006).Themean(90%)CIfortheratioofCmaxfed/fastedwas0.859(0.711to1.037).Themean(90%CI)fortheratiooffed/fastedAUC0-infforthe12.5mgdosewas100.9(97.7to104.1)%;andthemean(90%CI)fortheratiooffed/fastedAUC0-infforthe25mgdosewas97.1(94.9to99.3)(StudySYR-322-CPH-007).Themean(90%CI)fortheratiooffed/fastedCmaxforthe12.5mgdosewas122.7(112.1to134.3)%;andthemean(90%CI)fortheratiooffed/fastedCmaxforthe25mgdosewas107.1(97.6to117.5)%(StudySYR-322-CPH-007).Fooddecreasedtheexposuretoa100mgsingledoseofalogliptin:LSmean(90%CI)forAUC0-∞0.953(0.938to0.968)andCmax0.856(0.798to0.917)(StudySYR-322-005).DoseproportionalityTherewasdoseproportionalityforAUCandCmaxfroma12.5mgoraldosethroughtoa50mgoraldose(StudySYR-